Project Summary: The overall goal of this proposal is to understand the role of the skin in generation of Th2 effector cells. While it is clear that Th2 cells play a major role in atopic disease, the factors governing initiation of Th2 responses to environmental allergens are not well defined. This investigator has previously identified the skin as a prime site for Th2 sensitization to soluble protein antigen, and has shown that these epicutaneously induced Th2 responses are uniquely reliant upon IL-13, rather than IL-4.Studies outlined in this proposal will elucidate the mechanism behind this IL-13 dependent Th2 generation in the cutaneous environment. Preliminary studies have also identified a role for the innate immune system in generation of Th2 responses following epicutaneous exposure to protein antigen. Specfically, epicutaneously induced Th2 responses are abrogated in the absence of MyD88, an intracellular signaling molecule utilized by members of the IL-1/TLR (Toll-like receptor) family of innate immune system receptors. The hypotheses to be tested in this proposal are that: 1) The relatively unique role for IL-13 during epicutaneous Th2 induction relates either to the preferential production of IL-13 by cells in the skin or to a difference between cutaneous dendritic cells and those at other sites with regard to their receptivity to or dependence on IL-13 for activation; and 2) innate immune system signals contribute to the production of IL-13 needed for epicutaneous Th2 induction. These hypotheses will be tested in the following Specific Aims: 1) To determine the role of IL-13 in Th2 responses induced by epicutaneous exposure to soluble protein antigen; and 2) To determine the role of the innate immune system in Th2 generation in the cutaneous environment. Relevance: Along with asthma and other allergic diseases, the incidence of atopic dermatitis (eczema) has risen dramatically over the past few decades, with approximately 17% of school aged children in the United States being affected. Our data suggest that the skin may repesent a previously underappreciated site for systemic Th2 sensitization, possibly eventuating in allergic airway disease. Understanding how exposure of the skin to environmental allergens might contribute to an individual's subsequent development of hayfever and asthma could lead to novel approaches to preventing the development of these conditions.